Rapidly degrading embolic particles with therapeutic agent release

ABSTRACT

In accordance with one aspect, embolic particles are provided which comprise sub-particles that comprise a therapeutic agent of low solubility dispersed in a matrix that comprises a biodegradable polymer. Other aspects pertain to injectable compositions that comprise such particles and to methods of treatment that employ such injectable compositions. Still other aspects pertain to methods of making such particles.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.14/614,928, filed Feb. 5, 2015; which claims priority under 35 U.S.C. §119 to U.S. Provisional Application Ser. No. 61/939,794 filed Feb. 14,2014, the entire disclosures of which are herein incorporated byreference.

FIELD OF THE INVENTION

The invention relates to polymeric embolic particles for injection thatexhibit therapeutic agent release.

BACKGROUND OF THE INVENTION

Many clinical situations benefit from regulation of the vascular,lymphatic or duct systems by restricting the flow of body fluid orsecretions. For example, the technique of embolization involves theintroduction of particles into the circulation to occlude blood vessels,for example, so as to either arrest or prevent hemorrhaging or to cutoff blood flow to a structure or organ. Temporary occlusion of bloodvessels is desirable for managing various diseases and conditions.

In one example of an embolization procedure, local anesthesia is firstgiven over a common artery. The artery is then percutaneously puncturedand a catheter is inserted and fluoroscopically guided into the area ofinterest. An angiogram is then performed by injecting contrast agentthrough the catheter. An embolic agent is then deposited through thecatheter. The embolic agent is chosen, for example, based on the size ofthe vessel to be occluded, the desired duration of occlusion, and/or thetype of disease or condition to be treated (e.g., hypervascular tumors,uterine fibroids, etc.), among others factors. A follow-up angiogram maybe performed to determine the specificity and completeness of thearterial occlusion. Blocking the blood supply to the tissue is intendedto result in shrinkage and/or death of the tissue.

Embolic therapy is gently used to treat late stage liver cancer forpatients that are not candidates for liver transplantation or liverresection. There are currently a number of specific embolic therapiesavailable. These therapies include bland embolization, transarterialchemoembolization (TACE) and drug eluting bead (DEB) therapy.

Bland embolization utilizes embolic particles injected into arteriesfeeding the tumor to stop blood flow to the tumor, thus causingnecrosis. The embolic particles do not contain a drug.

TACE involves initial localized injections of a chemotherapeutic drugfollowed immediately by injection of embolic particles to prevent drugreflux and to cause embolization. TACE provides two modes of action,embolization (necrosis) and chemotherapy, and it is more effective thanBLAND embolization. However with TACE there is a lack of sustained drugrelease since it involves a single injection of a drug. In addition TACEis cumbersome to perform since it involves two separate steps in theprocedure.

DEB combines the drug into the embolic particles and like TACE involvestwo modes of action. Unlike TACE, DEB offers the potential for sustaineddrug release. However, currently available DEB products show in-vitrorapid release (i.e., within hours) of the drug from the embolicparticles. Also, current DEB therapy utilizes biostable particles sore-treatment is not possible. Clinically, DEB has been shown to besomewhat superior in efficiency to TACE. None of the embolic therapiesis currently curative, although in a majority of cases a single therapydelays tumor progression.

SUMMARY OF THE INVENTION

In accordance with one aspect of the invention, embolic particles areprovided, which comprise therapeutic-agent-containing sub-particlesdispersed in a biodegradable polymer matrix. The embolic particles areconfigured such that, upon administration to a body lumen of a subject,the biodegradable polymer matrix degrades, leading to the release of thesub-particles. In some embodiments, the sub-particles are alsoconfigured such that the sub-particles remain localized at the injectionsite for a period of time after the biodegradable polymer matrixcompletely degrades.

Other aspects of the invention pertain to injectable compositions thatcomprise such particles and to methods of treatment that employ suchinjectable compositions.

Still other aspects of the invention pertain to methods of making suchparticles.

These and various additional aspects and embodiments of the presentinvention will become immediately apparent to those of ordinary skill inthe art upon review of the Detailed Description and any appended claimsto follow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1C are schematic illustrations of three states of an embolicparticle in a vessel as a function of time, in accordance with anembodiment of the present invention.

FIGS. 2A-2B are schematic illustrations of two states of an embolicparticle in a vessel as a function of time, in accordance with anembodiment of the present invention.

FIG. 3 is a schematic illustration of an embolic particle, and amagnified schematic illustration of one of its sub-particles, inaccordance with an embodiment of the present invention.

FIG. 4 is a micrograph of a PLGA embolic particle, which containsdihydrate crystals.

FIG. 5 is a micrograph of as received as-received crystalline anhydrouspaclitaxel powder.

FIG. 6 is a micrograph of the crystalline anhydrous paclitaxel powder ofFIG. 5 after incubation overnight in water at 37° C.

DETAILED DESCRIPTION

In some aspects, the present disclosure providestherapeutic-agent-releasing embolic particles that are capable ofembolizing arteries in a tumor before rapidly degrading. In certainbeneficial embodiments, the particle persists long enough to cause tumornecrosis while at the same time degrading quickly enough to avoidsignificant vessel thrombosis, thereby leaving open the possibility of asubsequent embolic treatment at the same site. In certain beneficialembodiments, the embolic particles provide extended therapeutic agentrelease long after degradation.

In accordance with various embodiments, the present disclosure providesembolic particles that comprise therapeutic-agent-containingsub-particles dispersed in a biodegradable polymer matrix. The embolicparticles are configured such that, upon administration to a body lumenof a subject, the biodegradable polymer matrix degrades, leading to therelease of the sub-particles.

For example, the embolic particles may be configured such that uponadministration to a body lumen of a subject (e.g., a blood vessel suchas an artery, etc.), the biodegradable polymer degrades at a rate thatis sufficiently slow to embolize the vessel and cause necrosis ofdownstream tissue (e.g., embolizing the vessel for at least 60 minutes),while at the same time degrading at a rate that is sufficiently rapid torestore blood flow in the vessel within 48 hours of administration, morepreferably within 36 hours of administration, so as to reduce thelikelihood of thrombosis.

In various embodiments, the therapeutic agent continues to be releasedlocally after the degradation of the biodegradable polymer matrix, forexample, continuing to be released for an extended time (i.e., at for atleast 7 days, up to 1 month, or more) after the biodegradable polymermatrix has completely degraded. For example, the embolic particles maycontain therapeutic-agent-containing sub-particles at least a portion ofwhich are configured to remain localized at the embolism site andcontinue to release therapeutic agent for an extended time aftercomplete degradation of the biodegradable polymer matrix.

As defined herein, “complete degradation” is the point where 10 wt % orless, preferably 5 wt % or less, even more preferably 2 wt % or less, ofthe original biodegradable polymer weight (i.e., the biodegradablepolymer weight at the time of injection) remains at the embolism site.

In this regard, it is desirable to re-establish blood flow after theembolic particle causes necrosis, so that the vessel can be re-treatedat a later time. Stoppage of blood flow to the tumor only needs to occurfor a short period of time to result in tumor necrosis, after whichblockage is no longer needed and, in fact, interferes with theapplication of additional therapy to the same site. In many cases,however, it is beneficial to provide extended localized therapeuticagent release to the tumor, which normally is not possible with rapidlydegrading particles, because the therapeutic agent is released andcarried downstream from the site. In certain embodiments, the presentdisclosure provides therapeutic-agent-containing sub-particles that areconfigured to remain localized at the embolism site, thereby overcomingthe conundrum of designing a fast-degrading particle with sustainedtherapeutic agent delivery.

The injectable particles may be used to treat various diseases andconditions in a wide variety of subjects. Subjects include vertebratesubjects, particularly humans and various warm-blooded animals,including pets and livestock. As used herein, “treatment” refers to theprevention of a disease or condition, the reduction or elimination ofsymptoms associated with a disease or condition, or the substantial orcomplete elimination of a disease or condition.

The injectable particles of the disclosure may vary in shape. In certainembodiments, they are substantially spherical, for example, having theform of a perfect (to the eye) sphere or the form of a near-perfectsphere such as a prolate spheroid (a slightly elongated sphere) or anoblate spheroid (a slightly flattened sphere), among other regular orirregular near-spherical geometries. In embodiments where the particlesare substantially spherical, at least half of the particles (50% ormore, for example, from 50% to 75% to 90% to 95% or more of a particlesample) may have a sphericity of 0.8 or more (e.g., from 0.80 to 0.85 to0.9 to 0.95 to 0.97 or more). The sphericity of particles can bedetermined, for example, using a Beckman Coulter RapidVUE Image Analyzerversion 2.06 (Beckman Coulter, Miami, Fla.). Briefly, the RapidVUE takesan image of continuous-tone (gray-scale) form and converts it to adigital form through the process of sampling and quantization. Thesystem software identifies and measures the particles in an image. Thesphericity of a particle, which is computed as Da/Dp (where Da=√(4A/π);Dp=P/π; A=pixel area; P=pixel perimeter), is a value from zero to one,with one representing a perfect circle. A particle is “spherical” if ithas a sphericity of 0.8 or more (e.g., from 0.80 to 0.85 to 0.9 to 0.95to 0.97 or more).

The injectable particles of the present disclosure can varysignificantly in size, with typical widths (e.g., the diameter of asphere, the diameter of a rod or fiber, etc.) of the particles ranging,for example, from 10 to 1000 microns (μm) (e.g., from 10 to 20 to 50 to100 to 150 to 200 to 500 to 1000 microns), more typically from 20 to 200microns.

Therapeutic-agent-containing sub-particles for use in the embolicparticles of the present disclosure may vary significantly in size, withtypical widths (e.g., the diameter of a sphere, the diameter of a rod orfiber, etc.) of the sub-particles being less than the width of theembolic particle that they occupy, more typically less than 0.5 times,less than 0.1 times, less than 0.03 times, less than 0.01 times, lessthan 0.003 times, or even less than 0.001 times the width of the embolicparticle.

In various embodiments, the sub-particles may range, for example, from10 nm to 10,000 nm in width (e.g., from 10 nm to 25 nm to 50 nm to 100nm to 250 nm to 500 nm to 1000 nm to 2500 nm to 5,000 nm to 10,000 nm inwidth), among other values.

In various embodiments, the sub-particles are needle-like particleswhich have an aspect ratio (length:width) ranging from 10:1 to 25:1 to50:1 to 100:1 to 250:1 to 500:1 to 1000:1 or more. In some of theseembodiments, the length of such sub-particles may be on the order of thewidth of the embolic particle, ranging, for example, from 0.1 times to0.25 times to 0.5 times to 1.0 times the width of the embolic particle,or more.

As used herein, “polymers” are molecules that contain multiple copies ofone or more types of constitutional species, commonly referred to asmonomers. The number of monomers within a given polymer may vary widely,ranging, for example, from 5 to 10 to 25 to 50 to 100 to 1000 to 10,000or more constitutional units.

As used herein, a polymer is “biodegradable” if it undergoes bondcleavage along the polymer backbone in vivo, regardless of the mechanismof bond cleavage (e.g., enzymatic breakdown, hydrolysis, oxidation,etc.).

Beneficial biodegradable polymers for use in the embolic particles ofthe present disclosure include (a) polyanhydride homopolymers andcopolymers such as poly(adipic anhydride), poly(suberic anhydride),poly(sebacic anhydride), poly(dodecanedioic anhydride), poly(maleicanhydride), poly[1,3-bis(p-carboxyphenoxy)methane anhydride], andpoly[alpha,omega-bis(p-carboxyphenoxy)alkane anhydrides] such aspoly[1,3-bis(p-carboxyphenoxy)propane anhydride],poly[1,3-bis(p-carboxyphenoxy)hexane anhydride], and poly(sebacicacid-co-1,3-bis(p-carboxyphenoxy) propane), among others, (b) poly(orthoester) homopolymers and copolymers, including as class I poly(orthoesters), class II poly(ortho esters), class III poly(ortho esters), andclass IV poly(ortho esters), among others, and (c) polysaccharideshomopolymers and copolymers such as starch and alginates, among others.

The injectable particles of the present disclosure may benon-crosslinked or they may be covalently and/or non-covalentlycrosslinked. Thus, in some embodiments, crosslinking agents such ascovalent crosslinking agents or ionic crosslinking agents may be presentin the injectable particles, whereas in other embodiments crosslinkingagents are absent from the particles. In some embodiments the particlesmay be crosslinked by exposure to radiation (e.g., gamma or e-beamradiation), which may occur in conjunction with sterilization ofparticles.

Beneficial therapeutic agents for use in the embolic particles of thepresent disclosure include anti-tumor agents. Beneficial therapeuticagents for use in the embolic particles of the present disclosureinclude those having low solubility therapeutic agents (i.e., having asolubility of less than 1 g/l in water at 25° C., and less than 100 mg/lin some embodiments). Particularly beneficial are low solubilityanti-tumor agents such as paclitaxel, everolimus, and sorafenib, amongothers. Typical therapeutic agent loadings range, for example, from 0.1wt % or less, to 0.2 wt % to 0.5 wt % to 1 wt % to 2 wt % to 5 wt % to10 wt % to 20 wt % or more of the dry weight of the composition.

Several embodiments using starch as a biodegradable polymer andpaclitaxel as a therapeutic agent will now be discussed. It should benoted that, although a polysaccharide (i.e., starch) is used indiscussing various embodiments to follow, other biodegradable polymersare suitable for the practice of the present disclosure. It should alsobe noted that, although paclitaxel is used in the various embodiments tofollow, other therapeutic agents are suitable for the practice of thepresent disclosure.

Starch is known to biodegrade by an enzymatic process involving amylase.The time of complete degradation for starch embolic particles may beless than two days, for example, ranging from 1 hr to 2 hrs to 4 hrs to6 hrs to 12 hrs to 18 hrs to 24 hrs to 36 hrs to 48 hrs. Processes toprepare starch microspheres are known in the literature. See, e.g.,Patricia B. Malafaya et al., J Mater Sci: Mater Med (2006) 17: 371-377.

In certain embodiments of the present disclosure, a water-in-oilemulsion is formed in which starch is dissolved in an aqueous phase thatis dispersed in an oil phase. Amorphous paclitaxel sub-particles orcrystalline anhydrous paclitaxel sub-particles may also be dispersed inthe aqueous phase. (As discussed below, both amorphous and crystallineanhydrous paclitaxel particles can coalesce over time in the presence ofwater into needle-like dihydrate crystals. So long as the exposure ofthe amorphous or crystalline anhydrous paclitaxel particles to water iskept to a reasonable time period, e.g., less than 1 hour, significantcrystallization of the amorphous paclitaxel particles or conversion ofthe crystalline anhydrous paclitaxel particles to crystalline dihydratepaclitaxel particles may be avoided; one can also reduce the processingtemperatures to inhibit crystallization.) Water-in-oil emulsionformation may be enhanced by the addition of a surfactant, for example,a non-ionic surfactant such as Tween 80, Span 80, or a suitable lowmolecular weight polymer such as polyvinyl alcohol orpolyvinylpyrrolidone, among others. A homogenizer or sonicator can beused to reduce the dispersed phase to a desired size. A crosslinkingagent such as trisodium trimetaphosphate (TSTP), epichlorohydrin,glutaraldehyde or formaldehyde, among others, may be added to crosslinkthe starch in the dispersed aqueous phase and form embolic particles.For TSTP, the crosslinking reaction is initiated by raising the pH witha suitable basic solution (e.g., an NaOH solution) to activate thecrosslinking agent. The reaction is stopped by the addition of asuitable acidic solution (e.g., an HCl solution). Regardless of themethod of formation, once formed, the embolic particles, which contain adispersion of amorphous or crystalline anhydrous paclitaxelsub-particles in a starch matrix, may then be washed, isolated, sizedand lyophilized, as desired.

Sub-particles of amorphous paclitaxel may be obtained, for example, byfirst providing a solution of paclitaxel in a first solvent that is agood solvent for paclitaxel (e.g., tetrahydrofuran, dimethylformamide,dichloromethane, etc.), and then adding drops of this solution into asecond solvent that is miscible with the first solvent but which is apoor solvent for paclitaxel (e.g., heptane, hexane, toluene, etc.), withthe result being that the paclitaxel precipitates out of solution. Toaid in particle dispersibility, a surfactant such as Span 80 may beadded to the particles.

Sub-particles of as received crystalline anhydrous paclitaxel may beformed by milling of the as received crystalline anhydrous powder in ahigh frequency shaker with zirconium milling media.

It has been observed that for particles containing amorphous paclitaxelmicroparticles dispersed in a polymer matrix (i.e., PLGA), uponincubation in water at 37C, the amorphous paclitaxel particles coalescewithin hours into large, needle-like dihydrate crystals. An example ofcrystalline paclitaxel formation in a PLGA particle is shown in FIG. 4(scale=1 micron).

It has also been observed that for as-received crystalline anhydrouspaclitaxel powder dispersed in water at 37° C., the crystallineanhydrous paclitaxel particles coalesce within hours to largeneedle-like dihydrate crystals. Examples of as-received crystallineanhydrous paclitaxel powder, and crystalline dihydrate formed afterincubation of the crystalline anhydrous paclitaxel powder overnight inwater at 37° C., are shown in FIGS. 5 and 6, respectively.

Regardless of the method by which the amorphous or crystalline dihyratepaclitaxel sub-particles are dispersed within the starch matrix, uponintroduction to an aqueous in vivo environment (e.g., injection into apatient), water will be available over a time sufficient for dihydrateformation, and the amorphous or crystalline anhydrous paclitaxelmicroparticles within the embolic particles may coalesce intoneedle-like dihydrate crystals.

As additional time passes in vivo, the starch is broken down leavingneedle-like dihydrate crystals behind in the blood vessel. Crystallinedihydrate paclitaxel is very lipophilic (aqueous solubility<1 g/L), andthe dihydrate crystalline polymorph can act as a drug depot due to itsslow dissolution profile, which can transpire over the course of about amonth.

Use of such particles is shown schematically in FIGS. 1A-1C. When anembolic particle 110 p is injected into an artery (e.g., an artery 200feeding a tumor) as shown in FIG. 1A, the particle 110 p stops bloodflow to the tissue (e.g., tumor tissue) downstream of the embolicparticle, causing tumor necrosis. Upon being exposed to water in theartery, the amorphous or crystalline anhydrous paclitaxel in theparticles starts to convert to dihydrate crystal forming an embolicparticle 100 c with crystalline paclitaxel needles as shown in FIG. 1B.When the starch particle degrades as shown in FIG. 1C, at least aportion of the crystalline paclitaxel needles 120 s remain in thevasculature, thereby acting as drug depot and providing sustained drugrelease to the tumor while blood flow is restored.

Alternatively, dispersed amorphous or crystalline anhydrous paclitaxelwithin the embolic particles can be subjected to a vapor annealing inethanol ex vivo to efficiently convert the amorphous or crystallineanhydrous paclitaxel to dihydrate crystals. In this way, one does nothave to rely on in-vivo conversion of amorphous or crystalline anhydrouspaclitaxel to dihydrate crystals. A suitable vapor annealing process isdescribed in U.S. Patent Application Pub. No. 2011/0015664 A1 to Kangaset al.

In other embodiments of the present disclosure, embolic particles areformed, in which oil sub-particles are dispersed throughout thebiodegradable polymer (e.g., starch) matrix. The oil sub-particles maycontain, for example, therapeutic agent nanoparticles (e.g., crystallinepaclitaxel nanoparticles) dispersed in a suitable oil, for example, aniodinated oil such as an iodinated plant-based oil or an iodinatedanimal-based oil. In a particular embodiment, Lipiodol® (also known asethiodized oil and Ethiodol®) may be employed. Lipiodol is an iodinatedpoppy seed oil, which is used as a contrast agent. Lipiodol is alsoknown to have high affinity to liver tumors (see, e.g., Sun Wook Shin,Korean J Radiol 10(5), September/October 2009, 425-434) with residencetime in the tumor of weeks (as observed by fluoroscopy), and it iscommonly used as a contrast agent in TACE procedures. In the presentdisclosure, nanoparticles of therapeutic agent (e.g., crystallinepaclitaxel nanoparticles) are dispersed in lipiodol, which is, in turn,dispersed in a starch matrix. Typical sizes for the nanoparticles oftherapeutic agent range, for example, from 5 to 500 nm (e.g., from 5 nmto 10 nm to 25 nm to 50 nm to 100 nm to 250 nm to 500 nm), among otherpossibilities. The oil acts as a tumor specific carrier of thetherapeutic agent nanoparticles. As the starch degrades, it releases theoil microspheres. One portion of the oil microspheres may washdownstream and lodge/adsorb in the microvasculature (vessels<10 umdiameter) while another portion of the oil microspheres may be depositedon the artery in proximity to where the embolic particle degrades,thereby allowing for sustained release (e.g., days to weeks) oftherapeutic agent from the oil into the tissue.

Crystalline dihydrate paclitaxel nanoparticles in lipiodol can be formedby a milling process. Starting with as-received crystalline anhydrouspaclitaxel powder from Indena USA Inc., Seattle Wash., USA, thecrystalline anhydrous paclitaxel is treated with water to convert to thestable crystalline dihydrate form. Then the crystalline dihydratepaclitaxel and lipiodol from Guerbet LLC, Bloomington, Ind., USA aremilled with zirconia milling media using a high speed shaker.Sub-particles of the resulting paclitaxel-containing lipiodol can beformed in an aqueous phase (e.g., starch dissolved in water) bycombining the paclitaxel-containing lipiodol with a volume of theaqueous phase and emulsifying the mixture, for example, using ahomogenizer or sonicator, forming an oil-in-water emulsion. Thiscomposition may then be added to a volume of a suitable oil phase andemulsified, for example, using a homogenizer or sonicator, forming anoil-in-water-in-oil double emulsion. The starch in the dispersed aqueousphase may be crosslinked (e.g., as described above). Regardless of themethod of formation, once formed, the embolic particles, which contain adispersion of therapeutic-agent-containing iodinated oil sub-particlesin a starch matrix, may then be washed, isolated, sized and lyophilized,as desired.

The use of such embolic particles is shown schematically in FIGS. 2A-2B.When the embolic particles 110 p are injected into an artery 200 (e.g.,an artery feeding a tumor) the particle stops blood flow to the tumor asshown in FIG. 2A, causing tumor necrosis. When the starch in the embolicparticle 110 p degrades as shown in FIG. 2B, blood flow is restored.Degradation of the starch in the embolic particle 110 p also results inthe release of the lipiodol sub-particles 120 s containing thecrystalline paclitaxel nanoparticles, and at least a portion of thesub-particles 120 s may form deposits 120 c on the artery wall 200 inproximity to the position where the starch particle degraded, allowingfor sustained release of paclitaxel from the oil into the surroundingtumor. Other sub-particles may flow downstream and lodge inmicrovasculature where paclitaxel is also released into the tumortissue.

Referring now to FIG. 3, according to another embodiment of the presentdisclosure, starch particles 110 p are prepared which contain proteinstabilized therapeutic agent sub-particles, more particularly,paclitaxel nanoparticles 120 x stabilized with albumin 10 a. Otherproteins that can be used are gelatin and plant based proteins such asgliadin, legumin, soy protein isolate and whey protein isolate, amongothers. The FDA approved drug Abraxane is an aqueous dispersion ofalbumin stabilized paclitaxel nanoparticles (mean diameter ˜130 nm).Pre-clinical and clinical studies of IV infusion of Abraxane have shownthat tumor uptake of paclitaxel is significantly greater than that of astandard cremophor/paclitaxel IV infusion (see, e.g., A. Sparreboom etal., Clin Cancer Res 2005; 11:4136-4143). This is believed to be due inpart to favorable binding of the albumin to tumor proteins. Byincorporating albumin stabilized paclitaxel into starch particles one isable to both embolize the tumor (leading to necrosis) and provide for amuch higher localized dose of paclitaxel than is possible with systemicinfusion of albumin-stabilized paclitaxel particles. Particles may beformed by creating a water-in-oil emulsion in which the aqueous phasecontains dissolved starch and dispersed albumin-stabilized paclitaxelparticles. Upon forming an emulsion in which the aqueous phase isdispersed in an oil phase, the starch in the dispersed aqueous phase iscrosslinked (e.g., as described above), thereby forming embolicparticles. Regardless of the method of formation, once formed, theembolic particles, which comprise a dispersion of protein-stabilizedtherapeutic agent particles (e.g., albumin-stabilized paclitaxelparticles) in a starch matrix, may then be washed, isolated, sized andlyophilized, as desired.

In certain embodiments, the particles of the present disclosure willoptionally include imaging contrast agents in amounts useful to enhancein vivo imaging of the particles. (It is noted that some of the embolicparticles described above will inherently contain a contrast agent inthe form of lipiodol.) Examples of imaging agents include (a) contrastagents for use in conjunction with magnetic resonance imaging (MRI),including contrast agents that contain elements with relatively largemagnetic moment such as Gd(III), Dy(III), Mn(II), Fe(III) and compounds(including chelates) containing the same, such as gadolinium ionchelated with diethylenetriaminepentaacetic acid, and (b) contrastagents for use in connection with x-ray fluoroscopy, including metals,metal salts and oxides (particularly bismuth salts and oxides), andiodinated compounds, among others.

The embolic particles of the present disclosure may be stored andtransported in wet or dry form, and are preferably stored andtransported in a sterile dry form. In addition to biodegradable embolicparticles and optional contrast agent as described herein, embolicparticle compositions may also optionally contain additional agents, forexample, selected from one or more of the following, among others: (a)tonicity adjusting agents such as sugars (e.g., dextrose, lactose,sucrose, etc.), polyhydric alcohols (e.g., glycerol, propylene glycol,mannitol, sorbitol, etc.) and inorganic salts (e.g., potassium chloride,sodium chloride, etc.), among others, (b) suspension agents includingvarious surfactants, wetting agents, and polymers (e.g., albumen, PEO,polyvinyl alcohol, block copolymers, etc.), among others, and (c) pHadjusting agents including various buffer solutes.

Dry or wet embolic particle compositions may be shipped, for example, ina syringe, catheter, vial, ampoule, or other container. Dry forms may bemixed with a suitable liquid carrier (e.g. sterile water for injection,physiological saline, phosphate buffer, a solution containing an imagingcontrast agent, etc.) prior to administration. In this way theconcentration of the composition to be injected may be varied as desiredby the healthcare practitioner in charge of the procedure. Wet forms(e.g., aqueous suspensions) may also be mixed with a suitable liquidcarrier (e.g. sterile water for injection, physiological saline,phosphate buffer, a solution containing contrast agent, etc.) prior toadministration, allowing the concentration of administered particles (aswell as other optional agents) in the suspension to be reduced prior toinjection, if so desired by the healthcare practitioner in charge of theprocedure. One or more containers of liquid carrier may also be suppliedand shipped, along with the dry or wet particles, in the form of a kit.Kits may also include one or more instruments to assist in delivery suchas catheters (e.g., microcatheters), guidewires, and so forth. Kits mayalso include printed material with one or more of the following: (i)storage information and (ii) instructions regarding how to administerthe embolic particles to a subject.

As indicated above, in some embodiments embolic particles in accordancewith the present disclosure may be used in treating solid tumors, suchas renal carcinoma, bone tumors and liver tumors, among various others.Embolization may be conducted as an enhancement to chemotherapy orradiation therapy. In other embodiments, the particles may be used totreat benign tumors. For example, fibroids, also known as leiomyoma,leiomyomata or fibromyoma, are the most common benign tumors of theuterus.

The present disclosure also encompasses various methods of administeringthe particulate compositions of the disclosure to effect embolization.One skilled in the art can determine the most desirable way ofadministering the particles depending on the type of treatment and thecondition of the patient, among other factors. Methods of administrationinclude, for example, percutaneous techniques as well as other effectiveroutes of administration. For example, the particulate compositions ofthe present disclosure may be delivered through a syringe or through acatheter, for instance, a Tracker® microcatheter (Boston Scientific,Natick, Mass., USA), which can be advanced over a guidewire, a steerablemicrocatheter, or a flow-directed microcatheter (MAGIC, Balt,Montomorency, France). In some embodiments, anticoagulants such asheparin or warfarin are given to the patient during and immediately postprocedure, to reduce the likelihood of thrombus formation at theinjection site.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of any appended claims without departing from the spirit andintended scope of the invention.

The invention claimed is:
 1. An embolic particle comprisingsub-particles dispersed in a matrix that comprises a biodegradablepolymer, wherein the sub-particles comprise a therapeutic agent of lowsolubility, wherein the therapeutic agent is an anti-tumor agent,wherein said sub-particles comprise particles that comprise theanti-tumor agent dispersed in oil or wherein said sub-particles compriseprotein stabilized particles that comprise the anti-tumor agent, whereinthe upon administration to a blood vessel, the matrix of the embolicparticle biodegrades and the sub-particles remain localized in the bloodvessel and continue to release the anti-tumor agent locally in the bloodvessel after the matrix has completely degraded.
 2. The embolic particleof claim 1, wherein upon administration to a blood vessel, the particlecompletely biodegrades within a period of one hour to two days.
 3. Theembolic particle of claim 1, wherein said particle ranges between 20 and200 microns in width.
 4. The embolic particle of claim 1, wherein saidsub-particles range between 10 nm and 10,000 nm in width.
 5. The embolicparticle of claim 1, wherein said biodegradable polymer is selected frompolyanhydrides, poly(ortho esters) and polysaccharides.
 6. The embolicparticle of claim 1, wherein said biodegradable polymer comprises starchand wherein the starch is crosslinked to stabilize the embolic particle.7. The embolic particle of claim 1, wherein said sub-particles compriseneedle-like particles that comprise said therapeutic agent.
 8. Theembolic particle of claim 1, wherein said sub-particles compriseparticles of amorphous paclitaxel, particles of crystalline anhydrouspaclitaxel or needle-like particles of crystalline paclitaxel dihydrate.9. The embolic particle of claim 1, wherein said sub-particles comprisecrystalline paclitaxel particles dispersed in iodinated oil.
 10. Theembolic particle of claim 1, wherein said sub-particles comprisecrystalline paclitaxel particles dispersed in iodinated poppy seed oil.11. The embolic particle of claim 1, wherein said sub-particles compriseprotein stabilized paclitaxel particles.
 12. The embolic particle ofclaim 1, wherein said sub-particles comprise albumen stabilizedpaclitaxel particles.
 13. An injectable medical composition comprisingembolic particles in accordance with claim 1 in wet or dry form.
 14. Theinjectable medical composition of claim 13, further comprising atonicity adjusting agent.
 15. The injectable medical composition ofclaim 13, wherein said injectable medical composition is disposed withina glass container or a preloaded medical device.
 16. A method ofembolization comprising injecting the injectable medical composition ofclaim 13 into a patient.
 17. The method of embolization of claim 16,further comprising administering an anticoagulant to the patient.
 18. Akit comprising: (a) the medical composition of claim 13 and (b) one ormore of the following: (i) a catheter, (ii) a guidewire and (iii) aliquid carrier.
 19. The embolic particle of claim 1, wherein saidsub-particles comprise nanoparticles of said therapeutic agent dispersedin iodinated oil.
 20. The embolic particle of claim 19, wherein uponadministration to a blood vessel, the particle completely biodegradeswithin a period of one hour to two days, wherein said particle rangesbetween 20 and 200 microns in width, and wherein said sub-particlesrange between 10 nm and 10,000 nm in width.